Extreme genetic diversity in Plasmodium falciparum helps malaria parasites evade host immunity and impedes malaria vaccine development. Naturally acquired immunity to malaria is thought to represent the accumulation of protective immune responses to a repertoire of antigens and, importantly, to different variants of these antigens. But we remain largely ignorant of precisely which antigens and how many and which variants of these antigens must be recognized by which sorts of immune responses to afford natural or vaccine-induced protection. This project is largely focused on improving this understanding. Building on results of previous clinical translational research conducted in rural Mali, West Africa, we propose to further elucidate the mechanisms underlying both naturally acquired and vaccine-induced immune responses that protect against malaria infection and disease, and to use this knowledge to inform the development of broadly protective malaria vaccines. We will exploit recent technological advances to address at the genome-wide level questions that could previously be approached only one or a few genes at a time, developing new tools to assess immune responses against variant antigens and epitopes. In a prospective cohort study of children at risk for malaria infection and disease and in separate clinical trials of malaria vaccines, molecular and immunological correlates of natural and vaccine-induced protective immunity to P. falciparum infections and disease will be identified. This research is expected to provide information that will elucidate mechanisms underlying naturally acquired malaria immunity, improve the next generation of malaria vaccines and increase prospects for malaria elimination in Africa.